RR is defined as the proportion of patients with complete response + partial response (CR + PR] based on a patient's best response. The proportion of RR (CR+PR) will be estimated along with a one-sided lower 95% exact confidence bound to allow an informal assessment of the null hypothesis (RR=40%) based on binomial probabilities.

Patients will be monitored for systemic, renal, gastrointestinal, hematologic, neurological and liver toxicities. Adverse events will be tabulated by organ system and severity. Proportions will be estimated along with 95% exact confidence intervals.

Patients receive bevacizumab IV over 30-90 minutes on days 1 and 15, capecitabine PO BID on days 1-14, and temozolomide PO QD on days 10-14. Courses repeat every 28 days in the absence of disease progression or unacceptable toxicity.

Drug: capecitabine

Given PO

Other Names:

CAPE

Ro 09-1978/000

Xeloda

Drug: temozolomide

Given PO

Other Names:

SCH 52365

Temodal

Temodar

TMZ

Biological: bevacizumab

Given IV

Other Names:

anti-VEGF humanized monoclonal antibody

anti-VEGF monoclonal antibody

Avastin

rhuMAb VEGF

Detailed Description:

PRIMARY OBJECTIVES:

I. To estimate if the combination of capecitabine and temozolomide with bevacizumab for metastatic or unresectable neuroendocrine tumors will improve response rate (RR) by 62% over historical controls (null RR of 40% to true RR 65%).

II. Assess the toxicities using Common Terminology Criteria for Adverse Events (CTCAE) v4.0.

Patients receive bevacizumab intravenously (IV) over 30-90 minutes on days 1 and 15, capecitabine orally (PO) twice daily (BID) on days 1-14, and temozolomide PO once daily (QD) on days 10-14. Courses repeat every 28 days in the absence of disease progression or unacceptable toxicity.

After completion of study treatment, patients are followed up patients are followed up for 1 year.

Eligibility

Ages Eligible for Study:

18 Years and older (Adult, Senior)

Genders Eligible for Study:

Both

Accepts Healthy Volunteers:

No

Criteria

Inclusion Criteria:

Patients must have histologically confirmed pancreatic neuroendocrine tumors that are considered well- or moderately- differentiated

Patients must have metastatic or unresectable disease

Patients with prior surgical resection who develop radiological or clinical evidence of metastatic cancer do not require separate histological or cytological confirmation of metastatic disease unless an interval of > 5 years has elapsed between the primary surgery and the development of metastatic disease. Clinicians should consider biopsy of lesions to establish diagnosis of metastatic disease if there is substantial clinical ambiguity regarding the nature or source of apparent metastases.

Prior sunitinib and everolimus will be permitted. A wash-out period of 2 weeks is required prior to first dose on this study.

Prior liver directed therapies will be permitted (ie. chemoembolization, radioembolization) as long as target lesions in the liver have demonstrated growth since the liver directed treatment.

Prior peptide receptor radionuclide therapy (PRRT) will be permitted as long as target lesions in the liver have demonstrated growth since the liver directed treatment.

Low-dose aspirin (<= 325 mg/d) may be continued in subjects at higher risk for arterial thromboembolic disease.

Patients must have a primary or metastatic lesion measurable in at least one dimension by Modified RECIST criteria v1.1 (see Section 4.2) within 4 weeks prior to entry of study.

Prior full field radiotherapy <= 4 weeks or limited field radiotherapy <= 2 weeks prior to enrollment. Patients must have recovered from all therapy-related toxicities. The site of previous radiotherapy should have evidence of progressive disease if this is the only site of disease.

Diagnosis of another malignancy, unless the patient was diagnosed at least 3 years earlier and has been disease-free for at least 6 months following the completion of curative intent therapy, specifics as follows:

Curatively resected non-melanomatous skin cancer

Curatively treated cervical carcinoma in situ

Patients with organ-confined prostate cancer with no evidence of recurrent or progressive disease based on prostate-specific antigen (PSA) values are also eligible for this study if hormonal therapy has been initiated or a radical prostatectomy has been performed.

Other primary solid tumor curatively treated with no known active disease present and no treatment administered for the last 3 years.

Concurrent use of other investigational agents and patients who have received investigational drugs <= 4 weeks prior to enrollment.

Known hypersensitivity to capecitabine, temozolomide, or any component of the formulation and or a known deficiency of dihydropyrimidine dehydrogenase.

General Medical Exclusions

Subjects meeting any of the following criteria are ineligible for study entry:

Inability to comply with study and/or follow-up procedures.

Current, recent (within 4 weeks of the first infusion of this study), or planned participation in an experimental drug study .

Pregnancy (positive pregnancy test) or lactation- breast feeding Lack of of effective means of contraception (men and women) in subjects of child-bearing potential.

Uncontrolled systemic fungal, bacterial, viral, or other infection (defined as exhibiting ongoing signs/symptoms related to the infection and without improvement, despite appropriate antibiotics or other treatment).

Known history of HIV, HBV, or HCV

Current, ongoing treatment with full-dose warfarin. However patients may be on stable doses of a low molecular weight heparin are allowed (ie. Lovenox).

History of hemoptysis (>= 1/2 teaspoon of bright red blood per episode) within 1 month prior to Day 1.

Evidence of bleeding diathesis or significant coagulopathy (in the absence of therapeutic anticoagulation).

Major surgical procedure, open biopsy, or significant traumatic injury within 28 days prior to Day 1 or anticipation of need for major surgical procedure during the course of the study.

Core biopsy or other minor surgical procedure, excluding placement of a vascular access device, within 7 days prior to Day 1.

History of abdominal fistula or gastrointestinal perforation within 6 months prior to Day 1.

Serious, non-healing wound, active ulcer, or untreated bone fracture.

Proteinuria: Patients are allowed to have 0, trace, or 1+ protein by urine dipstick or urinalysis to enroll, if >= 2+ must check 24h urine protein and must be < 1g to start study.

Known hypersensitivity to any component of bevacizumab.

Contacts and Locations

Choosing to participate in a study is an important personal decision. Talk with your doctor and family members or friends about deciding to join a study.
To learn more about this study, you or your doctor may contact the study research staff using the Contacts provided below.
For general information, see Learn About Clinical Studies.

Please refer to this study by its ClinicalTrials.gov identifier: NCT01525082